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Genetic counseling: Cowden Syndrome
Cowden Syndrome Contracting *What were you told about why you were referred? *What would you like to learn today? *Do you have any questions or concerns that you would like us to address? Medical and Family Histories * Breast cancer? Endometrial cancer? Benign or malignant tumor of thyroid? *Renal cell carcinomas, melanoma, glioblastoma? *Hamartomas of colon, GI tract? * Macrocephaly? Mental retardation? *Facial or oral mucocutaneous lesions (trichilimmomas)? *Fibrocystic breast disease? *Lipomas or fibromas? * Lhermitte-Duclos disease (hamartoma of cerebellum) - altered gait or seizures? Etiology *Multiple hamartoma syndrome with high risk for benign and malignant tumors of breast, thyroid, and endometrium *Part of PTEN hamartoma tumor syndrome (PHTS) **Includes Cowden syndrome, Bannayan-Riley-Ruvalcaba, Proteus syndrome, and Proteus-like syndrome **Causes hamartomas and cancer due to PTEN mutations *PTEN mutations and Cowden syndrome: **Mutations identified in approximately 80% of individuals with a clinical diagnosis **Located at 10q23.3 **PTEN gene is a tumor suppressor gene **Mediates cell-cycle arrest and apoptosis **Part of subclass of dual-specificity phosphatases that remove phosphates from tyrosine, serine, and threonine **May play a role in cell migration **Has 9 exons **Germline mutations have been found throughout gene except exon 9 **76% of mutations result in truncated protein, haploinsufficiency, or dysfunctional protein *True prevalence is unknown due to underdiagnosis **Diagnosis of Cowden sydrome difficult to establish ***Variable presentation ***Symptoms may be subtle **Estimated to be 1 in 200,000 - probably higher Clinical Features *Multiple hamartoma syndrome **High risk for benign and malignant tumors of thyroid breast and endometrium **Usually presents by late 20's - over 90% of affected people have some features **Mucocutaneous features present by 30's (99%) ***Trichilemmomas ***Papillomatous papules ***Acral and plantar keratosis *Macrocephaly or dolichocephaly common *Tumor risks **25-50% lifetime risk of breast cancer ***Average age 38-46 years at diagnosis ***Up to 67% risk for benign breast disease ***Male breast cancer has been reported **About 10% lifetime risk for thyroid cancer ***Usually follicular, sometimes papillary - never medullary ***Not clear if average age of diagnosis is same as for general population ***Benign multinodular goiter, adenomatous nodules, and follicular adenomas in up to 75% of patients **May be 5-10% risk for endometrial cancer ***Not well defined ***Benign uterine fibroids are common **Skin cancers, renal cell carcinomas, and brain tumors seen occasionally **Lhermitte-Duclos disease ***Rare central nervous system tumor ***Called cerebellar dysplastic gangliocytoma **Colorectal cancer has been observed rarely in families Genetic approach * three-generation family tree (focus on macrocephaly, breast/thyroid disease, learning disability) * AD, 50% risk (risk of having of Bannayan-Riley-Ruvalcaba as well as Cowden) * Mucocutaneous signs (found >90%) could be the only manifestations * 2/3 have breast and/or thyroid disorder Treatment/Management Options *Increased breast cancer screening **Women should have monthly self exams, annual clinical exams at age 25, and annual mammograms at 30 (or 5 years before youngest age at diagnosis) **Men should do monthly self breast exams *Endometrial cancer screening **Annual blind repel (suction) biopsies in premenopausal women beginning at age 35 (or 5 years before youngest age at diagnosis) **Annual transvaginal ultrasound exam with biopsy of suspicious findings for postmenopausal women *Comprehensive annual physical exam **For men and women starting at age 18 (or 5 years before youngest component cancer diagnosis in family) **Focus on skin changes and thyroid changes, including baseline ultrasound *Follow American Cancer Society for colon cancer screening **GI tract may have hamartomatous polyps not thought to increase cancer risk **Baseline colonoscopy at 50 years unless symptoms arise earlier **Annual fecal occult blood testing with sigmoidoscopy every 5 years or colonoscopy every 10 years *Annual urinalysis to detect renal carcinoma Diagnosis *Consensus criteria for clinical diagnosis have been established (International Cowden Consortium 2000) **Pathognomonic criteria ***Defining characteristic of Cowden syndrome ***Mucocutaneous lesions ****Trichilemmomas on face ****Acral keratoses (thickened area of skin that may be red, yellow, or brown) ****Papillomatous lesions ****Mucosal lesions **Major criteria ***Breast cancer ***Thyroid cancer ***Macrocephaly *** Lhermitte-Duclos disease (LDD) ***Endometrial carcinoma **Minor criteria ***Other thyroid lesions ***Mental retardation ***Hamartomatous intestinal polyps ***Fibrocystic breast disease ***Lipomas ***Fibromas ****GU tumors or malformations (uterine fibroids and renal cell carcinoma) **Criteria for diagnosis ***Pathognomic mucocutaneous lesions if there are: ****Six or more facial papules, with three or more trichilemmoma ****Cutaneous facual papules and oral mucosal papillomatosis ****Oral mucosal papillomatosis and acral keratoses ****Six or more palmo-plantar keratoses ***Macrocephaly or LDD with one other major criteria ***One major and three minor criteria ***Four minor criteria **If affected family member has already been identified, diagnosis requires: ***A pathognomonic mucocutaneous lesion ***Any one major criterion with or without minor criteria ***Two minor criteria *Pathologic review to confirm histopathology of lesions *Molecular genetic testing **Failure to detect mutation does not does not exclude clinical diagnosis **Full sequencing of PTEN gene ***Available clinically ***Virtually all missense mutations believed to be deleterious ***Genotype-phenotype correlation ****Families with PTEN mutations more likely to develop breast disease than those without identified mutations ****Missense mutations and mutations 5' to or within phosophatase core are associated with more severe phenotype **Southern blotting and monochromosomal hybrid analysis available by research Differential Diagnosis *Other PHTS syndromes **'Banayan-Riley-Ruvalcaba (BRR)' ***Mutational spectra overlap, autosomal dominant (AD), PTEN mutations 60% ***Complex, highly variable disorder with much in common with Cowden (macrocephaly, association with breast, thyroid, endometrial and gut hamartomas) ***Diagnosis relies on macrocephaly, hamartomatous intestinal polyposis, vascular malformations, lipomas, and pigmented macules of glans penis ***Hypotonia, gross motor and learning-speech delay, may have seizures, mild hypertelorism. **'Proteus syndrome' ***Highly variable and appears to only affect some organs or tissues ***Sporadic occurrence, progressive course, and connective tissue nevi ***Can cause disproportionate limb growth ***Recently a proteus-like syndrome has been described but is as yet undefined *'Juvenile polyposis syndrome' **Causes hamartomatous polyps in GI tract and high colorectal cancer risk **Clinical diagnosis of exclusion **Two susceptibility genes have been identified *'Peutz Jeghers syndrome' **High risk of intestinal carcinomas and breast cancers **Pigmentation of peri-oral region is defining characteristic **Polyps are often symptomatic *Possibly also consider NF1 or Nevoid basal cell carcinoma (Gorlin) syndrome Psychosocial Issues *Anxiety surrounding new diagnosis of disorder that cannot be "cured" *Requires patient compliance with screening measures - burden of many appointments *Family thoughts on causes of cancer or other indications *Past experiences with cancer in family and friends Resources *Cowden's Syndrome Foundation :Phone: 734-944-8313 :Web: communities.msn.com/cowdensyndrome/supportinfo.msnw :Email: Rosalita@msn.com *American Cancer Society :Phone: 800-227-2345 :Web: www.cancer.org *The National Alliance of Breast Cancer Organizaations :Phone: 888-806-2226 :Web: www.nabco.org :Email: NABCOinfo@aol.com See also Genetic counseling: Lhermitte–Duclos disease References *Eng, Charis. "Cowden Syndrome." Journal of Genetic Counseling (1997) 6 :81. *Eng, Charis. "Will the Real Cowden Syndrome Please Stand Up?" Journal of Medical Genetics (2000) 37:0-2. *Schneider, Katherine. Counseling About Cancer (2002). *"PTEN Hamartoma Tumor Syndrome (PHTS)." GeneReviews. www.genereviews.org Notes The information in this outline was last updated in 2002. Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling Category:Genetic counseling